Methods of synthesis of (1r,2r,5r)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein

ABSTRACT

Provided herein are methods and intermediates for making (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride, which are useful for the preparation of compounds useful for the treatment of a disease, disorder, or condition associated with the JNK pathway.

This application is a continuation of U.S. patent application Ser. No.16/992,219, filed Aug. 13, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/258,802, filed Jan. 28, 2019, now U.S. Pat. No.10,774,033, issued Sep. 15, 2020, which is a continuation of U.S. patentapplication Ser. No. 15/746,853, filed Jan. 23, 2018, now U.S. Pat. No.10,252,981, issued Apr. 19, 2019, which is a U.S. national stageapplication of International Patent Application No. PCT/US2016/043511,filed Jul. 22, 2016, which claims the benefit of priority to U.S.Provisional Application Ser. No. 62/196,363, filed Jul. 24, 2015, eachof which is incorporated herein by reference in its entirety and for allpurposes.

FIELD

Provided herein are methods and intermediates for making(1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride, which are usefulfor the preparation of compounds useful for the treatment of a disease,disorder, or condition associated with the JNK pathway.

BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. (SeeCohen, Nature, 1:309-315 (2002), Gaestel et al. Curr. Med. Chem. 14:2214-223 (2007); Grimminger et al. Nat. Rev. Drug Disc. 9(12):956-970(2010)). Various protein kinase inhibitors have been used clinically inthe treatment of a wide variety of diseases, such as cancer and chronicinflammatory diseases, including rheumatoid arthritis and psoriasis.(See Cohen, Eur. J. Biochem., 268:5001-5010 (2001); Protein KinaseInhibitors for the Treatment of Disease: The Promise and the Problems,Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167(2005)).

JNK is a ubiquitously expressed serine/threonine kinase belonging,together with ERK (extracellular-regulated kinase) and p38, to thefamily of mitogen-activated protein kinases (MAPKs). (Kyriakis J M, Sci.STKE (48):pe1 (2000); Whitmarsh A J, et al. Sci. STKE (1):pe1 (1999);Schramek H, News Physiol. Sci. 17:62-7 (2002); Ichijo H, Oncogene18(45):6087-93 (1999)). MAPKs are important mediators of signaltransduction from the cell surface to the nucleus, using phosphorylationcascades to generate a coordinated response by a cell to an externalstimulus by phosphorylation of selected intracellular proteins,including transcription factors. Additionally, JNK also phosphorylatesnon-nuclear proteins, for example, IRS-1, and Bcl-2 family members.(Davis R J, Trends Biochem. Sci. 9(11):470-473 (1994); Seger R et al.,FASEB J.; 9(9):726-35 (1995); Fanger G R et al., Curr. Opin. Genet.Dev.; 7(1):67-74 (1997)).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. The compound chemicallynamed2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide(alternatively named2-[(1,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide;and referred to herein as “Compound I”), an inhibitor of the JNKpathway, is disclosed in U.S. Patent Application Publication No.2013/0029987, published on Jan. 31, 2013, International Pub. No. WO2012/145569 and U.S. patent application Ser. No. 14/608,314, filed Jan.29, 2015, the entireties of each of which are incorporated by referenceherein. Accordingly, there remains a need for new processes for thepreparation of Compound I.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

SUMMARY

Provided herein are processes and intermediates useful for thepreparation of Compound I:

having the name2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide,which is useful for the treatment of a disease, disorder, or conditionassociated with the INK pathway.

In particular, provided herein are processes for making a compound offormula (A):

having the name (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride.

Provided is a method for preparing a compound of formula (A),

comprises the steps of:

-   -   (a) contacting a compound of formula (1),

with a compound of formula (2),

-   -   in the presence of a Lewis Acid in a solvent to provide a        compound of formula (3),

-   -   (b) contacting the compound of formula (3) of step (a) with an        aqueous base to provide a compound of formula (4),

-   -   (c) contacting the compound of formula (4) of step (b) with DMF        and a chlorinating agent in an organic solvent, followed by        treatment of the resulting acid chloride derivative with aqueous        ammonia to provide a compound of formula (5),

-   -   (d) contacting the compound of formula (5) of step (c) with an        aqueous solution of NaOH and NaOCl to provide a compound of        formula (6),

-   -   (e) contacting the compound of formula (6) of step (d) with        (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent to        provide a compound of formula (7),

-   -   (f) contacting the compound of formula (7) of step (e) with an        aqueous base, followed by treatment of the resulting free base        with Boc₂O in an organic solvent to provide a compound of        formula (8),

-   -   (g) contacting the compound of formula (8) of step (f) with a        mixture of a reducing agent, a chiral auxiliary and a Lewis acid        in a solvent, followed by treatment with an oxidant in the        presence of a base to provide a compound of formula (9),

and

-   -   (h) contacting the compound of formula (9) of step (g) with a        solution of hydrochloric acid in a solvent to provide the        compound of formula (A). In one embodiment, the Lewis acid of        step (a) is AlCl₃. In a further embodiment, the solvent of        step (a) is DCM. In one embodiment, the base of step (b) is        NaOH. In one embodiment, the chlorinating agent of step (c) is        SOCl₂. In a further embodiment, the organic solvent of step (c)        is DCM. In one embodiment, the solvent of step (e) is MeOH. In        one embodiment, the base of step (f) is NaOH. In a further        embodiment, the organic solvent of step (f) is DCM. In one        embodiment, the reducing agent of step (g) is NaBH₄. In a        further embodiment, the chiral auxiliary of step (g) is        α-pinene. In a particular embodiments, the Lewis acid of        step (g) is BF₃.Et₂O. In another particular embodiment, the        solvent of step (g) is THF. In still another embodiment, the        oxidant of step (g) is H₂O₂. In a specific embodiment, the base        of step (g) is NaOH. In one embodiment, the solvent of step (h)        is IPA.

In certain aspects, Compound I is useful for inhibiting a kinase in acell expressing said kinase, for example JNK1 or JNK2. In other aspects,Compound I is useful for treating or preventing a condition treatable orpreventable by inhibition of a JNK pathway, as described herein. Inanother aspect, Compound I is useful for treating or preventing one ormore disorders selected from interstitial pulmonary fibrosis, systemicsclerosis, scleroderma, chronic allograft nephropathy, antibody mediatedrejection, or lupus. In yet another aspect, Compound I is useful fortreating or preventing liver fibrotic disorders, or diabetes and/ormetabolic syndrome leading to liver fibrotic disorders, as describedherein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a ¹H NMR spectrum of Compound (A) in D₂O.

FIG. 2 depicts an expanded (˜0.2-3.6 ppm) ¹H NMR spectrum of Compound(A) in D₂O.

FIG. 3 depicts a HPLC chromatogram of Compound (A).

FIG. 4 depicts a chiral GC chromatogram of Compound (A).

DETAILED DESCRIPTION Definitions

As used herein, and in the specification and the accompanying claims,the indefinite articles “a” and “an” and the definite article “the”include plural as well as single referents, unless the context clearlyindicates otherwise.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with amounts or weight percentsof ingredients of a process, mean an amount or weight percent that isrecognized by one of ordinary skill in the art to provide an effectequivalent to that obtained from the specified amount, or weightpercent. In certain embodiments, the terms “about” and “approximately,”when used in this context, contemplate an amount or weight percentwithin 30%, within 20%, within 15%, within 10%, or within 5%, of thespecified amount or weight percent.

“JNK” means a protein or an isoform thereof expressed by a JNK1, JNK2,or JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J.,Sluss, H. K., Derijard, B. and Davis, R. J. The EMBO J. 15:2760-2770(1996)).

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder is a condition treatable or preventableby inhibition of a INK pathway, as described herein. In anotherembodiment, the disorder is selected from interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus. In yet anotherembodiment, the disorder is a liver fibrotic disorder, or diabetesand/or metabolic syndrome leading to liver fibrotic disorders, asdescribed herein. In some embodiments, the disorder is a liver fibroticdisorder, such as non-alcoholic steatohepatitis, steatosis (i.e. fattyliver), cirrhosis, primary sclerosing cholangitis, primary biliarycirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosiscoincident with chronic or repeated alcohol ingestion (alcoholichepatitis), with infection (e.g., viral infection such as HCV), withliver transplant, or with drug induced liver injury (e.g., acetaminophentoxicity). In some embodiments, “treating” means an alleviation, inwhole or in part, of a disorder, disease or condition, or symptomsassociated with diabetes or metabolic syndrome leading to liver fibroticdisorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fattyliver), hepatitis or cirrhosis, or a slowing, or halting of furtherprogression or worsening of those symptoms. In one embodiment, thesymptom is jaundice.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition. In one embodiment, thedisorder is a condition treatable or preventable by inhibition of a JNKpathway, as described herein. In another embodiment, the disorder isselected from interstitial pulmonary fibrosis, systemic sclerosis,scleroderma, chronic allograft nephropathy, antibody mediated rejection,or lupus. In one embodiment, the disorder is a liver fibrotic disorder,or diabetes or metabolic syndrome leading to liver fibrotic disorders,as described herein, or symptoms thereof.

“Patient” or “subject” is defined herein to include animals, such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys,chickens, turkeys, quails, or guinea pigs and the like, in oneembodiment a mammal, in another embodiment a human. In one embodiment, asubject is a human having or at risk for having interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus. In another, asubject is a human having or at risk for having liver fibrotic disordersor diabetes or metabolic syndrome leading to liver fibrotic disorders,or a condition, treatable or preventable by inhibition of a INK pathway,or a symptom thereof.

Compound (A)

As described in U.S. Patent Application Publication No. 2013/0029987,published on Jan. 31, 2013, International Pub. No. WO 2012/145569 andU.S. patent application Ser. No. 14/608,314, filed Jan. 29, 2015, theentireties of each of which are incorporated by reference herein,compounds of formula I can be prepared as shown in Scheme A.

The processes provided herein relate to methods for making a compound offormula (A):

having the name (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride,and intermediates useful in said processes.

It should be noted that if there is a discrepancy between a depictedstructure and a name given to that structure, the depicted structure isto be accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

Methods for Making Compound (A)

By way of example and not limitation, the compound of formula (A) can beprepared as outlined in Scheme 1 shown below, as well as in the examplesset forth herein.

In one aspect, provided herein are methods for preparing a compound offormula (A):

the methods comprising contacting a compound of formula (9):

with hydrochloric acid in a solvent.

In some embodiments, the solvent is methanol, 2-propanol (IPA), ether ordioxane. In one embodiment, the solvent is 2-propanol (IPA).

In some embodiments, the methods further comprise preparing a compoundof formula (9):

the methods comprising contacting a compound of formula (8):

with a mixture of a reducing agent, a chiral auxiliary and a Lewis acidin a solvent, followed by treatment with an oxidant in the presence of abase.

In one embodiment, the reducing agent is NaBH₄. In another embodiment,the chiral auxiliary is α-pinene. In another embodiment, the Lewis acidis BF₃.Et₂O. In one embodiment, the solvent is THE or EtOH. In anotherembodiment, the solvent is THF. In one embodiment, the oxidant is H₂O₂or oxone. In another, the oxidant is H₂O₂. In one embodiment, the baseis NaOH.

In some embodiments, the methods further comprise preparing a compoundof formula (8):

the methods comprising contacting a compound of formula (7):

with an aqueous base, followed by treatment of the resulting free basewith Boc₂O in an organic solvent, optionally in the presence of a secondbase.

In one embodiment, the aqueous base is aqueous NaOH. In one embodiment,the organic solvent is DCM or ether. In another embodiment, the organicsolvent is DCM. In one embodiment, the second base is triethylamine.

In some embodiments, the methods further comprise preparing a compoundof formula (7):

the methods comprising contacting a compound of formula (6):

with (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent.

In one embodiment, the solvent is methanol.

In some embodiments, the methods further comprise preparing a compoundof formula (6):

the methods comprising contacting a compound of formula (5):

with an aqueous solution of NaOH and NaOCl.

In some embodiments, the methods further comprise preparing a compoundof formula (5):

the methods comprising contacting a compound of formula (4):

with DMF and a chlorinating agent in an organic solvent, followed bytreatment of the resulting acid chloride derivative with aqueousammonia.

In one embodiment, the chlorinating agent is oxalayl chloride or SOCl₂.In one embodiment, the chlorinating agent is SOCl₂. In one embodiment,the organic solvent is DCM.

In some embodiments, the methods further comprise preparing a compoundof formula (4):

the methods comprising contacting a compound of formula (3):

with an aqueous base.

In one embodiment, the base is LiOH or NaOH. In another embodiment, thebase is NaOH.

In some embodiments, the methods further comprise preparing a compoundof formula (3):

the methods comprising contacting a compound of formula (1):

with a compound of formula (2):

in a solvent, in the presence of a Lewis acid.

In one embodiment, the Lewis acid is AlCl₃. In one embodiment, thesolvent is DCM.

Intermediates useful in the processes provided herein include:

Utility of Compound I

Compound I has utility as a pharmaceutical to treat, prevent or improveconditions in animals or humans. In particular, Compound I is activeagainst protein kinases, particularly JNK1 and/or JNK2. Uses of CompoundI are disclosed in U.S. Patent Publication No. 2013/0029987, publishedJan. 31, 2013, which is incorporated by reference herein in itsentirety.

Abbreviations

The following abbreviations are used in descriptions and examples:

ACN: Acetonitrile

Boc: tert-Butoxycarbonyln-BuOH: n-ButanolDBTA: Dibenzoyl-D-tartaric acidDBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMAc:N,N-Dimethylacetamide DMF: N,N-Dimethylformide DMSO: Dimethylsulfoxide

EtOAc: Ethyl acetate

EtOH: Ethanol GC: Gas Chromatography IPA: 2-Propanol

IPAc: Isopropyl acetate

LC: Liquid Chromatography MeOH: Methanol

2-MeTHF: 2-Methyl tetrahydrofuranMS: Mass spectrometryMTBE: tert-Butyl methyl etherNMP: N-Methyl-2-pyrrolidoneNMR: Nuclear magnetic resonance

OR: Optical Rotation SFC: Supercritical Fluid Chromatography

Tf: Triflate or trifluoromethanesulfonyl

TFE: 2,2,2-Trifluoroethanol THF: Tetrahydrofuran SYNTHETIC EXAMPLES

The following synthetic examples, presented by way of illustration andnot limitation, show methods for the preparation of Compound (A).ACD/NAME (Advanced Chemistry Development, Inc., Ontario, Canada) wasused to generate names for chemical structures and Chemdraw(Cambridgesoft, Perkin Elmer, Waltham, Mass.) to draw the chemicalstructures. In certain cases, Chemdraw was used to generate names forchemical structures.

Example 1: Synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanolhydrochloride

Methyl 4-methylcyclohex-3-enecarboxylate (3): To a reactor was added DCM(2.5 L) and methyl acrylate (1) (500.0 g) at 20-25° C. under anatmosphere of nitrogen. After stirring for 5 min., the batch was cooledto 0° C., and isoprene (2) (593.4 g) was added over 5-10 min. Afterstirring for 5 min. at 25° C., anhydrous AlCl₃ (116.2 g) was added over60-90 min. while maintaining the temperature between 0-10° C. Afterstirring at 0-10° C. for 30 min., the batch was gradually warmed to 25°C. and stirred (≥3 h) at that temperature until IPLC indicated <1%unreacted methyl acrylate (1). Upon completion of the reaction, asindicated by HPLC, the batch was cooled to 0° C. and quenched with HClsolution (250 mL conc. HCl and 1750 mL water) over a period of 30-60min. while keeping the temperature below 10° C. during the quenchingperiod. The batch was allowed to warm up to 25° C., and was filteredthrough Hyflo to remove the undissolved solid while rinsing the residuewith DCM (500 mL). The filtrate was extracted with DCM (1 L), and thecombined organic layers were successively washed with 5% aqueous NaHCO₃(1 L) solution and brine (1 L). DCM was distilled out from the organicfraction at 40-50° C. under atmospheric condition to furnish crudemethyl 4-methylcyclohex-3-enecarboxylate (3) as a brown liquid (˜1200 g,quantitative yield, 85.54% purity by HPLC), which was used for the nextstep without purification.

4-Methylcyclohex-3-enecarboxylic acid (4): To a solution of NaOH (290.4g NaOH in 1800 mL water) in a reactor at 15-20° C. was slowly added4-methylcyclohex-3-enecarboxylate (3) (1200 g crude material from above;895.63 g considering 100% yield), while keeping the temperature below25° C. The batch was gradually warmed to 35-40° C. and the resultingclear solution was stirred (≥2 h) at that temperature until HPLCindicated <1% unreacted intermediate (3). Upon completion of thereaction, as indicated by HPLC, the batch was brought to 25° C. andquenched with water (900 mL). The aqueous mixture containing the productwas washed with DCM (2×900 mL). The aqueous layer was cooled to 0-10° C.and acidified with conc. HCl (630 mL) to pH 1-2 while keeping thetemperature below 20° C. After stirring the mixture for 10 min. at20-25° C., the product was extracted from the aqueous layer with DCM(2×900 mL). The combined organic layers were washed with water (900 mL).DCM was distilled out from the organic fraction at 40-45° C. and theresulting solid mass was vacuum dried for 1 h at 40-45° C. to furnish,upon cooling to room temperature, 4-methylcyclohex-3-enecarboxylic acid(4) (707.51 g, 86.90% yield based on HPLC, 85.28% purity by HPLC). Theproduct thus obtained was dissolved in DCM (750 mL) and used for thenext step without purification.

4-Methylcyclohex-3-enecarboxamide (5): To a reactor containing asolution of 4-methylcyclohex-3-enecarboxylic acid (4) in DCM from above(˜1614 g, containing ˜690 g of intermediate (4)) was added DMF (6.9 mL)at 25° C. under an atmosphere of nitrogen. After stirring the reactionfor 5 min., thionyl chloride (673.44 g) was added over a period of 30-60min. while keeping the temperature below 20° C. After stirring for 10min. at 15-20° C., the reaction was warmed to 25-30° C. and stirred (≥2h) at that temperature until TLC indicated <2% unreacted intermediate(4). Upon completion of the reaction, as indicated by TLC, the solventswere completely distilled out under vacuum. The resulting mixture wasvacuum dried for 30 min. at 35-40° C. and then brought to roomtemperature. The mass thus obtained was slowly added over a period of30-60 min. to an ice-cold solution (0-5° C.) of aqueous ammonia (2.76 L)in a separate reactor while keeping the temperature below 10° C. Afterstirring the reaction mixture for 30 min. at 0-10° C., the resultingresidue was filtered off, washed with water, and vacuum dried over air.The product was further dried in an air oven at 45-50° C. and brought toroom temperature to furnish 4-methylcyclohex-3-enecarboxamide (5) as anoff-white solid (604 g, 88.15% yield based on HPLC, 86.55% purity byHPLC), which was used for the next step without purification.

4-Methylcyclohex-3-enamine (6): To a solution of NaOH (481.68 g) andwater (2.16 L) in a reactor at −5° C. to 5° C. was added slowly asolution of 10.5% w/w sodium hypochlorite (4587.4 g) under an atmosphereof nitrogen. After stirring for 10 min.,4-methylcyclohex-3-enecarboxamide (5) (600 g) was gradually added inportions at −5° C. to 5° C. The reaction was stirred for 6 h at atemperature below 10° C., gradually warmed to 25° C. and stirred (≥5 h)at that temperature until HPLC indicated <5% unreacted intermediate (5).Upon completion of the reaction, as indicated by HPLC, toluene (1.2 L)was added. The mixture was cooled to 0-5° C. and acidified with conc.HCl (1.5 L) to pH 1-1.5 while keeping the temperature below 20° C. Afterstirring for 5 min., the organic layer was separated, and the aqueouslayer was washed with toluene (1.2 L). The aqueous layer was then cooledto 0-5° C., and basified with aqueous NaOH solution (2.0 kg NaOH and1340 mL H₂O) to pH>13 while keeping the temperature below 20° C. Theproduct was extracted with DCM (2×1.5 L), and the combined organiclayers were dried over sodium sulfate and filtered. DCM was distilledout from the filtrate at 40-60° C. under atmospheric conditions. Theresulting residue was cooled to room temperature to furnish4-methylcyclohex-3-enamine (6) (377.4 g, 78.74% yield based on HPLC,85.74% purity by HPLC), which was used for the next step withoutpurification.

(R)-4-Methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7): Asolution of (+)-dibenzoyl-D-tartaric acid monohydrate (1015.3 g) inmethanol (3 L) was gradually brought to reflux. To this refluxingsolution was slowly added a solution of 4-methylcyclohex-3-enamine (6)(300 g) in methanol (300 mL) over a period of 60-75 min. The reactionmixture was refluxed for 2 h and then gradually cooled to 25° C. over4-5 h. After stirring the reaction mixture for an additional 1 h at 25°C., the resulting residue was filtered, washed with methanol, and driedunder vacuum for 30 min. Chiral HPLC of the Boc protected product(prepared by converting an aliquot to the Boc derivative) indicated71.22% of the desired (R)-4-methylcyclohex-3-enaminehemi-dibenzoyl-D(+)-tartarate (7), and 28.72% of the correspondingS-isomer.

The crude product obtained above (˜645 g) was treated with(+)-dibenzoyl-D-tartaric acid monohydrate (123.1 g) and methanol (3.8L), and the resulting mixture was refluxed for 2 h, and then graduallycooled to 25° C. over 4-5 h. After stirring the reaction mixture for anadditional 1 h at 25° C., the resulting residue was filtered, washedwith methanol, and dried under vacuum for 30 min. Chiral HPLC of analiquot of the product that was converted to the BOC derivativeindicated 82.11% of the desired (R)-4-methylcyclohex-3-enaminehemi-dibenzoyl-D(+)-tartarate (7), and 17.82% of the correspondingS-isomer.

The crude product obtained above (˜480 g) was treated with(+)-dibenzoyl-D-tartaric acid monohydrate (93.3 g) and methanol (2.9 L),and the resulting mixture was refluxed for 2 h, and then graduallycooled to 25° C. over 4-5 h. After stirring the reaction mixture for anadditional 1 h at 25° C., the resulting residue was filtered, washedwith methanol, and dried under vacuum for 30 min. The product thusobtained was further dried in air oven at 45-50° C. to furnish(R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7) (220.5g, 28.5% yield, 97.81% purity by GC, melting point range: 205.2-206.3°C., OR: +110.0° (C=1% in acetic acid at 25° C.)); chiral HPLC indicated86.88% of the desired R-isomer and 13.12% of the corresponding S-isomer.

(R)-tert-Butyl (4-methylcyclohex-3-en-1-yl)carbamate (8): To a solutionof NaOH (124 g) and water (1200 mL) at 10-20° C. was slowly added(R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7) (300 g)while keeping the temperature below 25° C. After stirring the reactionmixture for 15 min., the resulting free base was extracted from theaqueous layer using DCM (2×300 mL, 1×150 mL). The organic layers werecombined, and the resulting solution (˜850 mL) was treated with Bocanhydride (236.8 g) at 0-5° C. The reaction mixture was allowed to warmto 25° C., and stirred (≥2 h) at that temperature until HPLC indicated<1% unreacted intermediate (7). Upon completion of the reaction, asindicated by HPLC, water (230 mL) was added, and the mixture was stirredfor 10 min. The organic layer was separated and washed with 2% aqueouscitric acid solution (230 mL) followed with water (230 mL). DCM wasdistilled out at 30-40° C. under vacuum, and the resulting pale yellowmass was vacuum dried for 30 min. at 40-45° C. to furnish (R)-tert-butyl(4-methylcyclohex-3-en-1-yl)carbamate (8) (216 g, 98.91% yield based onHPLC, 98.36% purity by HPLC), which contained 14.85% of thecorresponding S-isomer as indicated by chiral HPLC. The product thusobtained was taken in THE (437 mL), stirred for 10 min. to obtain aclear solution, and stored under an atmosphere of nitrogen for use inthe next step.

tert-Butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9): To asuspension of sodium borohydride (76.97 g) in THE (1290 mL) at 25° C.was slowly added (−)-α-pinene (582.07 g) over a period of 15 min. underan atmosphere of nitrogen. After cooling the reaction mixture to 0-5°C., boron trifluoride etherate (57%, 531.95 g) was added slowly over aperiod of 30-60 min. The reaction was allowed to warm to 25° C., stirredfor 8 h, and then treated with the solution of (R)-tert-butyl(4-methylcyclohex-3-en-1-yl)carbamate (8) in THE prepared above (623 g,containing 215 g of (8)). The resulting reaction mixture was stirred (≥3h) at 25° C. until HPLC indicated <1% unreacted intermediate (8). Aftercooling to 0-5° C., the reaction was quenched slowly by adding waterover a period of 30-60 min., followed by subsequent addition of aqueousNaOH (244.15 g NaOH and 716 mL water) and a solution of 48% hydrogenperoxide (432.36 g). The reaction mixture was gradually warmed to 25° C.and stirred for 3 h, after which a solution of sodium thiosulfate (75 gsodium thiosulfate and 75 mL water) was added. After stirring for 30min., a solution of citric acid (254 g of citric acid and 860 mL water)was added, and the mixture was stirred for an additional 30 min. afterwhich ethyl acetate was added (1290 mL). After stirring for 10 min., theorganic layer was separated and the aqueous fraction was extracted withethyl acetate (2×430 mL). The organic layers were combined and thesolvent was distilled out at 40-50° C. under vacuum. The resulting masswas vacuum dried for 1 h to afford quantitative yield of tert-butyl((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9) (858 g crude),which was used for the next step without purification.

(1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (A): A mixture oftert-butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9) fromabove (853 g, containing 233 g of (9)) and IPA-HCl (14% w/w solution;699 mL) was stirred (≥2 h) at 25° C. until HPLC indicated <1% unreactedintermediate (9). The solvent was distilled out at 40-60° C. undervacuum. Fresh IPA (233 mL) was added at 40-45° C. and the solvent wasagain distilled out at 40-60° C. under vacuum. After degassing for 30min. at 40-60° C., the resulting mass was treated with fresh IPA (699mL) and the mixture was stirred under nitrogen at 30-35° C. for 30 min.and then at 0-5° C. for an additional 30 min. The solid product wasfiltered at 0-5° C. and washed with chilled IPA. The resulting productwas dried under vacuum at 40-60° C. to afford ˜70 g crude product, whichcontained ˜96.49% of the desired RRR-isomer as indicated by chiral GC(other isomers were present as impurities in the amount of 2.06% (SSSisomer), 0.18% (SRR isomer), and 1.26% (RSS isomer)). IPA (3 L) wasadded and the resulting slurry was refluxed for 30 min. The mixture wasgradually cooled to 70-75° C., and the undissolved impurity was filteredoff and washed with IPA (140 mL). The solvent was distilled out at40-60° C. to afford a white mass which was gradually cooled to 25° C.and then treated with water (31.5 mL) and acetonitrile (31.5 mL). Theresulting mixture was heated at 75-80° C. for 10 min. to obtain a clearsolution, which was then treated slowly with acetonitrile (574 mL) at75-80° C. over a period of 1 h. After stirring for 15 min. at 75-80° C.,the resulting mass was cooled to 0-5° C. over 2-3 h and stirred at thattemperature for 30 min. The product was filtered under nitrogen at 0-5°C., and the solid cake was washed with chilled acetonitrile (70 mL) anddried under vacuum to afford the desired RRR isomer. The above processof precipitating the desired product out of a mixture of water andacetonitrile by addition of acetonitrile at 75-80° C. was repeated untilchiral-GC indicated the presence of no more than 0.5% of any othersingle isomer (SSS, SRR and RSS isomer). The product thus obtained wasfurther dried under vacuum at 40-60° C. to afford(1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (A) as a whitesolid (63 g, 37.4% yield, 100% purity by HPLC, melting point range:244.0-245.5° C., SOR: −31.2° (C=1% in MeOH at 25° C.)); chiral GCindicated 99.83% of the desired RRR-isomer and 0.17% of thecorresponding SSS-isomer. ¹H-NMR (D₂O) (400 MHz): δ 3.18-3.08 (m, 2H),2.15-2.12 (m, 1H), 1.86-1.83 (m, 1H), 1.72-1.68 (m, 1H), 1.32-1.16 (m,3H), 1.02-0.91 (m, 1H), 0.86-0.85 (d, 3H, J=6.4 Hz)

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

1-22. (canceled)
 23. A method for preparing a compound of formula (9):

the methods comprising contacting a compound of formula (8):

with a mixture of a reducing agent, a chiral auxiliary and a Lewis acidin a solvent, followed by treatment with an oxidant in the presence of abase.
 24. The method of claim 23, wherein the reducing agent is NaBH₄.25. The method of claim 23, wherein the chiral auxiliary is α-pinene.26. The method of claim 23, wherein the Lewis acid is BF₃.Et₂O.
 27. Themethod of claim 23, wherein the solvent is THE or EtOH.
 28. The methodof claim 23, wherein the solvent is THF.
 29. The method of claim 23,wherein the solvent is EtOH.
 30. The method of claim 23, wherein theoxidant is H₂O₂ or oxone.
 31. The method of claim 23, wherein theoxidant is H₂O₂.
 32. The method of claim 23, wherein the base is NaOH.33. The method of claim 23, wherein the reducing agent is NaBH₄, thechiral auxiliary is α-pinene, the Lewis acid is BF₃.Et₂O, and thesolvent is THF.
 34. The method of claim 33, wherein the oxidant is H₂O₂and the base is NaOH.
 35. The method of claim 23, wherein the compoundis tert-Butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate.